title: Immunotherapy with gene-modified T cells: limiting side effects provides new challenges.
abstract: Genetic tools have been developed to efficiently engineer T-cell specificity and enhance T-cell function. Chimeric antigen receptors (CAR) use the antibody variable segments to direct specificity against cell surface molecules. T-cell receptors (TCR) can redirect T cells to intracellular target proteins, fragments of which are presented in the peptide-binding groove of HLA molecules. A recent clinical trial with CAR-modified T cells redirected against the B-cell lineage antigen CD19 showed dramatic clinical benefit in chronic lymphocytic leukaemia patients. Similarly, impressive clinical responses were seen in melanoma and synovial cell carcinoma with TCR-modified T cells redirected against the melanocyte lineage antigen MART-1 and the testis-cancer antigen NY-ESO-1. However, on and off-target toxicity was associated with most of these clinical responses, and fatal complications have been observed in some patients treated with gene modified T cells. This review will discuss factors that might contribute to toxic side effects of therapy with gene modified T cells, and outline potential strategies to retain anticancer activity while reducing unwanted side effects.
authors.affiliation: Department of Immunology, Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Stauss
authors.forename: E C
authors.initials: EC
authors.lastname: Morris
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D060846:Cell Engineering; D019070:Cell Lineage; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D009369:Neoplasms / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
chemical_list: D018941:Antigens, CD19; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins